Synthesis and antibacterial activity of a new series of 3-[3-(substituted phenyl)-1-phenyl-1H-pyrazol-5-yl]-2H-chromen-2-one derivatives

Article abstract of DOI:10.3109/14756366.2011.622270

A series of 3-[3-(substituted phenyl)-1-phenyl-1H-pyrazol-5-yl]-2H-chromen- 2-one (4a-k) were synthesized by reaction of 3-[2,3-dibromo-3-(substituted phenyl)propanoyl]-2H-chromen-2-one (3 a-k) with phenyl hydrazine in presence of triethylamine in absolute ethanol, characterized by spectral data and screened for their in vitro antibacterial activity against gram-positive and gram-negative bacteria. Among the series, compounds 4d, 4h and 4i displayed an encouraging antibacterial activity profile as compared to reference standard drug ciprofloxacin against tested bacterial strains.

Full text of DOI:10.3109/14756366.2011.622270

Journal of Enzyme Inhibition and Medicinal Chemistry, 2012; 27(6): 849–853
© 2012 Informa UK, Ltd.
ISSN 1475-6366 print/ISSN 1475-6374 online
DOI: 10.3109/14756366.2011.622270
ReseaRch aRtIcle
Synthesis and antibacterial activity of a new series of
3-[3-(substituted phenyl)-1-phenyl-1H-pyrazol-5-yl]-2H-
chromen-2-one derivatives
Prashant Aragade1, R. Venkat Narayanan1, Veeresh Maddi2, Pankaj Patil1, Prashant Shinde3, and
Mohan Agrawal3
1RVS College of Pharmaceutical Science, Sulur, Coimbatore, Tamilnadu, India, 2KLES’s College of Pharmacy,
Vidyanagar, Hubli, Karnataka, India, and 3Sitabai ite College of Pharmacy, Shirur, Pune, Maharashtra, India
abstract
A series of 3-[3-(substituted phenyl)-1-phenyl-1H-pyrazol-5-yl]-2H-chromen-2-one (4a–k) were synthesized by reaction
of 3-[2,3-dibromo-3-(substituted phenyl)propanoyl]-2H-chromen-2-one (3 a-k) with phenyl hydrazine in presence of
triethylamine in absolute ethanol, characterized by spectral data and screened for their in vitro antibacterial activity
against gram-positive and gram-negative bacteria. Among the series, compounds 4d, 4hand 4i displayed an encouraging
antibacterial activity profile as compared to reference standard drug ciprofloxacin against tested bacterial strains.
Keywords: Antibacterial activity, ciprofloxacin, coumarin, pyrazole
Introduction
A continuous increase in the number of infections caused
by bacteria resistant to one or multiple antibiotic classes
poses a significant threat1,2 as it may lead to treatment fail-
ures and complication. One of the main driving forces for
development and spread of resistance is high antibiotic
consumption, reflected in resistance rates directly cor-
relating with the prescription of antimicrobial drugs3. To
overcome resistance, in addition to prudent use of avail-
able drugs, a constant effort to discover and develop new
agents with an improved spectrum of activity is required.
In drug-designing programmes, an essential com-
ponent of the search for new leads is the synthesis of
molecules, which is novel yet resembles known biologi-
cally active molecules by virtue of the presence of critical
structural features. Certain small heterocyclic molecules
act as highly functionalized scaffolds and are known
pharmacophore of a number of biologically active and
due to their biological activities and their potential appli-
cations as pharmacological agents. Several coumarin ring
systems bearing various substituents at the C-3 position
are widely distributed in nature and have been reported
to have anti-viral, anti-oxidant and anti-fungal activities.
Furthermore, most of compounds prepared from 3-acetyl
coumarin have anti-microbial, anti-inflammatory and anti-
oxidant activities6–10. e heterocyclic systems encompass-
ing pyrazoles are explored to the maximum extent owing to
their wide spectrum of pharmacological activities, such as
analgesic, anti-inflammatory, antipyretic, anti-depressant,
hypotensive, anti-cancer, antibacterial, anti-parasitic, and
anti-androgenic agents10–17. Special attention is warranted
towards the synthetic design and development of pyra-
zoles because of their high demand in academic and phar-
maceutical sectors, and in continuation of our previous
work in the synthesis of biologically active heterocycles6,10
we report herein synthesis of some new 3-[3-(substituted
phenyl)-1-phenyl-1H-pyrazol-5-yl]-2H-chromen-2-one
4a–k, for investigation of their antibacterial profile.
medicinally useful molecules4,5
.
Widespread interest in the chemistry of coumarins in a
large number of natural products has attracted the interest
Address for Correspondence: Mr. Prashant D. Aragade, M. Pharm, RVS College of Pharmaceutical Science, Sulur, Coimbatore-641 402,
Tamilnadu, India. Tel/Fax: 91 2138 222680. E-mail: prashant.argade@gmail.com
(Received 27 July 2011; revised 05 September 2011; accepted 07 September 2011)
849

850 P. Aragade et al.
then the solvent was removed in vacuum. e residue
was triturated with 10mL of ethanol until a precipitate is
formed. e precipitate was filtered off and crystallized
from appropriate solvents.
experimental procedure
All research chemicals were purchased from Sigma–
Aldrich (St. Louis, Missouri, MO, USA) or Lancaster Co.
(Ward Hill, MA, USA) and used as such for the reactions.
Solvents except laboratory reagent grade were dried
and purified according to the literature when necessary.
Reactions were monitored by thin-layer chromatography
(TLC) on pre-coated silica gel plates from E. Merck and
Co. (Darmstadt, Germany). Melting points of synthesized
compounds were determined in ermonik (Mumbai,
India) melting point apparatus and are uncorrected, UV
spectra were recorded on ermospectronic (Rochester,
NY, USA) and IR spectra were recorded on ermo
Nicolet IR200 FT-IR Spectrometer (Madison, WI, USA) by
General procedure for preparation of 3-[2,3-dibromo-
3-(substituted phenyl)propanoyl]-2H-chromen-2-one
derivatives (3a–k)20
A 3-[(2E)-3-substituted-prop-2-enoyl]-2H-chromen-2-one
(2a–k, 0.01mol) was dissolved in chloroform (100mL)
and bromine (0.01mol) in chloroform was added drop
wise with constant stirring. After the complete addition of
bromine solution, the reaction mixture was stirred for 12h.
Excess of chloroform was distilled off under reduced pres-
sure. us obtained solid was filtered, dried and washed
from hot ethanol.
1
using KBr pellets. e HNMR were recorded on Bruker
AVANCE 300 (Bruker, Rheinstetten/Karlsruhe, Germany)
using DMSO-d6 as solvent. Chemical shifts are reported
in δ ppm units with respect to tetramethylsilane (TMS) as
internal standard. e purity of compounds was examined
by TLC on silica gel plate using chloroform and methanol
(10:1) as mobile phase and iodine vapours as visualizing
agent. e starting material 3-acetyl coumarin 1 was syn-
thesized by a method reported earlier18.
General procedure for synthesis of 3-[3-(substituted
phenyl)-1-phenyl-1H-pyrazol-5-yl]-2H-chromen-2-one
(4a–k)
A
mixture of 3-[2,3-dibromo-3-(substituted phenyl)
propanoyl]-2H-chromen-2-one (3a–k, 0.01 mol) and
phenyl hydrazine (0.01 mol) was dissolved in ethanol
(150 mL) and triethylamine (10 mL). e reaction mix-
ture was heated under reflux for 12h. Excess of ethanol
was distilled off under reduced pressure and residue
was triturated with ice-cold water. e precipitated solid
was filtered, dried and purified by column chromatog-
raphy using silica gel (60–120) as stationary phase and
chloroform:methanol (10:1) as mobile phase. e physi-
co-chemical and spectral data of synthesized compounds
4a–k is summarized in Tables 1 and 2, respectively.
General procedure of preparation of
3-aryl-1-(3-coumarinyl)prop-2-en-1-ones (2a–k)19
A mixture of 3-acetyl coumarin (1, 0.01mol) and the vari-
ous substituted aromatic aldehydes (0.012mol) was dis-
solved in 10mL of n-butanol under heating; then 0.3mL
of glacial acetic acid and the same quantity of piperidine
were added. e reaction mixture was refluxed for 4 h and
Table 1. Physico-chemical data of 3-[3-(substituted phenyl)-1-phenyl-1H-pyrazol-5-yl]-2H-chromen-2-one derivatives 4a–k.
Ra
H-
Yield (%)
53
M. P. (0 C)
158-260
120-122
98-100
Rf b
0.38
0.27
0.48
0.24
0.46
0.25
0.36
0.32
0.29
0.33
0.42
Formula
M. W.
364
394
398
433
407
409
378
394
382
409
380
Compound
4 a
4 b
4 c
4 d
4 e
4 f
C24H16N2O2
C25H18N2O3
C24H15ClN2O2
C24H14 Cl2N2O2
C26H21N3O2
C24H15N3O4
C24H18N2O2
C25H18N2O3
C24H15FN2O2
C24H15N3O4
C24H16N2O3
4-OMe-
4-Cl-
83
76
2,4-(Cl)2-
4-NMe2-
3-NO2-
4-Me-
92
126-130
148-150
100-102
90-92
70
67
4 g
4 h
4 i
74
3-OMe-
4-F-
83
136-138
190-192
208-210
182-184
64
4 j
2-NO2-
4-OH-
71
4 k
76
Note: aAll compounds purified by column chromatography using chloroform:methanol (10:1) as mobile phase; bchloroform:methanol
10:1 as a mobile phase and iodine vapours as visualizing agent.
Journal of Enzyme Inhibition and Medicinal Chemistry

Synthesis of 3-(1H-pyrazol-5-yl)-2H-chromen-2-one derivatives 851
Antibacterial activity
Medium
e solid media Mullere Hinton agar (MHA; beef infusion
300 g/L, casein acid hydrolysate 17.5 g/L, starch 1.5 g/L,
agar 17 g/L and distilled water 1000 mL, adjusted to pH
7.4) was used for the antibacterial activity.
Test microorganisms
Two gram-positive bacteria namely, Staphylococcus
aureus (ATCC-25923), Bacillus subtilis (ATCC 6633) and
two gram-negative bacteria namely, Escherichia coli
(ATCC-25922), Pseudomonas aeruginosa (ATCC-27853)
were used for the antibacterial activity.
Scheme 1. Synthesis of 3-[3-(substituted phenyl)-1-phenyl-1H-
pyrazol-5-yl]-2H-chromen-2-one reagents and conditions: (a)
Ar-CHO, piperidine/n-butanol, reflux, 4h; (b) Br2/CHCl3, stir r.t.
12h; (c) PhNHNH2, TEA/ethanol, reflux, 12h.
Minimum inhibitory concentration21
e in vitro antibacterial activity for newly synthesized
compounds (4a–k) was evaluated using the conventional
agar-dilution method. Two-fold serial dilutions of the
compounds and reference drug (ciprofloxacin) were pre-
pared in MHA. Drugs (10.0mg) were dissolved in DMSO
(1mL) and the solution was diluted with water (9mL).
Further progressive double dilution with melted MHA was
performed to obtain the required concentrations of 128,
64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, 0.05 µg/mL. e bacte-
rial inocula were prepared by suspending 24h old bacte-
rial colonies from MHA media in 0.85% saline. e inocula
were adjusted to 0.5 McFarland Standard (1.5×108 CFU/
mL)22. e suspensions were then diluted in 0.85% saline
to give 107 CFU/mL. Petri dishes were spot-inoculated
with 1 µL of each prepared bacterial suspension (104 CFU/
spot) and incubated at 37°C for 24h. At the end of the incu-
bation period, minimum inhibitory concentration (MIC)
was determined, which is the lowest concentration of the
test compound that resulted in no visible growth on the
plate. A control test was also performed with test medium
supplemented with DMSO at the same dilutions as used in
the experiment, in order to ensure that the solvent had no
influence on bacterial growth.
phenyl hydrazine. Bromination of chalcones 2a–k was
carried out in chloroform using bromine in chloroform
to yield di-bromo compounds 3a–k, which were cyclized
with phenyl hydrazine in the presence of triethylamine
in absolute ethanol to afford the 3-[3-(substituted phenyl)-
1-phenyl-1H-pyrazol-5-yl]-2H-chromen-2-one 4a–k. e
physical properties of the synthesized compounds are
presented in Table 1. e structures and purity of the
compounds were confirmed by spectral data and thin
layer chromatography (Table 2).
Antibacterial activity
All newly synthesized compounds 4a–k were evalu-
ated for their in vitro antibacterial activity against two
gram-positive bacteria, namely Staphylococcus aureus
(ATCC-25923) and Bacillus subtilis (ATCC 6633), and two
gram-negative bacteria, namely Escherichia coli (ATCC-
25922)andPseudomonasaeruginosa(ATCC-27853)using
conventional agar-dilution method23. Ciproflaxacin was
used as a reference standard. e results of the in vitro
antibacterial activity screening of the test compounds
are summarized in Table 3. Among the series, three com-
pounds (4d, 4h and 4i) exhibited excellent antibacterial
activity against both gram-positive and gram-negative
bacteria, while the compound 4c showed moderate anti-
bacterial activity against the tested organisms. However,
all other compounds in the series were found to have less
or poor activity against both gram-positive and gram-
negative bacteria as compared to standard. e MIC was
recorded as the lowest concentration of a compound to
inhibit growth of the tested micro-organisms. In compar-
ing the MIC values with the standard (MIC = 0.5 µg/mL),
compounds 4d, 4h and 4i exhibit the most potent in vitro
antibacterial activity against all evaluated organisms.
Compounds 4d (MIC = 0.25–1 µg/mL), 4h (MIC = 0.25–
0.5 µg/mL) and 4i (MIC = 0.25–1 µg/mL) especially
showed high antibacterial activity, while compound 4c
(MIC = 0.5–2 µg/mL) showed respectable antibacterial
activity. e investigation of the structure–activity rela-
tionship revealed that the compounds with p-fluoro,
m-methoxy, p-chloro, and o, p-dichloro substituents at
the third position in the aromatic ring of the pyrazole
Results and discussion
Synthesis
e synthesis of 3-[3-(substituted phenyl)-1-phenyl-1H-
pyrazol-5-yl]-2H-chromen-2-one (4a–k) was carried out
as presented in Scheme 1. Starting material 3-acetyl-2-
H-chromen-2-one 1 was synthesized by the reaction of
salicylaldehyde with ethylacetoacetate in the presence
of a catalytic amount of piperidine at room tempera-
ture following the literature procedure18. e 3-[(2E)-3-
(substituted phenyl)prop-2-enoyl]-2H-chromen-2-one
(chalcones, 2a–k) were synthesized by Claisen–Schmidt
condensation of 3-acetyl-2H-chromen-2-one 1 with
various substituted benzaldehydes in the presence of a
mixture of piperidine and n-butanol. Efforts to convert
compounds 2a–k into target molecules 4a–k under a
variety of conditions were not successful. Hence, an alter-
native method was adopted. is involved the bromina-
tion of chalcones 2a–k and subsequent ring closure using
© 2012 Informa UK, Ltd.

852 P. Aragade et al.
Table 2. Spectral data of 3-[3-(substituted phenyl)-1-phenyl-1H-pyrazol-5-yl]-2H-chromen-2-one derivatives 4a–k.
Compound
4 a
R
UV (CH3OH)
IR (KBr, cm1)
1H-NMR (DMSO-d6 δ, ppm)
H-
1679.0 (coumarin, C=O), 1634.74
(C=N), 1491.00 (C=C).
7.72 (s, 1H, 4-H of coumarin), 7.02–7.48 (m, 14H,Ar-H),
6.7 (s, 1H, 4-H of pyrazole).
λ
λ
λ
λ
λ
λ
λ
λ
λ
λ
λ
max 290 (ε 14523)
4 b
4 c
4 d
4 e
4 f
4-OMe-
4-Cl-
1681.97 (coumarin, C=O), 1624.74 7.83 (s, 1H, 4-H of coumarin), 6.83–7.37 (m, 13H,Ar-H),
(C=N), 1490.05 (C=C). 6.8 (s, 1H, 4-H of pyrazole), 3.73 (s, 3H, -OCH3).
1682.05 (coumarin, C=O), 1614.43 7.57 (s, 1H, 4-H of coumarin), 7.02–7.42 (m, 13H,Ar-H),
(C=N), 1486.72 (C=C). 6.7 (s, 1H, 4-H of pyrazole).
1682.63 (coumarin, C=O), 1616.31 7.58 (s, 1H, 4-H of coumarin), 7.02–7.36 (m, 12H,Ar-H),
(C=N), 1484.97 (C=C). 6.56 (s, 1H, 4-H of pyrazole).
1673.65 (coumarin, C=O), 1604.94 7.72 (s, 1H, 4-H of coumarin), 6.65–7.30 (m, 13H,Ar-H),
(C=N), 1449.36 (C=C). 6.7 (s, 1H, 4-H of pyrazole), 2.85 (s, 6H, -N(CH3)2).
1685.23 (coumarin, C=O), 1611.11 7.82 (s, 1H, 4-H of coumarin), 7.02–8.41 (m, 13H,Ar-H),
(C=N), 1449.36 (C=C). 6.65 (s, 1H, 4-H of pyrazole).
1715.41 (coumarin, C=O), 1672.78 7.72 (s, 1H, 4-H of coumarin), 7.02–7.36 (m, 13H,Ar-H),
(C=N), 1552.98 (C=C). 6.76 (s, 1H, 4-H of pyrazole), 2.35 (s, 3H, -CH3).
1681.97 (coumarin, C=O), 1624.94 7.83 (s, 1H, 4-H of coumarin), 6.73–7.30 (m, 13H,Ar-H),
(C=N), 1490.05 (C=C). 6.8 (s, 1H, 4-H of pyrazole), 3.63 (s, 3H, -OCH3).
1682.05 (coumarin, C=O), 1614.43 7.75 (s, 1H, 4-H of coumarin), 7.02–7.46 (m, 13H,Ar-H),
(C=N), 1486.72 (C=C). 6.7 (s, 1H, 4-H of pyrazole).
1689.61 (coumarin, C=O), 1609.40 7.82 (s, 1H, 4-H of coumarin), 7.02–8.41 (m, 13H,Ar-H),
(C=N), 1458.55 (C=C). 6.65 (s, 1H, 4-H of pyrazole).
3208.00 (-OH), 1671.33 (coumarin, 7.72 (s, 1H, 4-H of coumarin), 6.79–7.31 (m, 13H,Ar-H),
C=O), 1607.79,1505.92 (C=C). 6.65 (s, 1H, 4-H of pyrazole), 5.28 (s, 1H, -OH).
max 272 (ε 18673)
max 302 (ε 12657)
max 286 (ε 16795)
max 276 (ε 17987)
max 286 (ε 15672)
max 282 (ε 17898)
max 292 (ε 12893)
max 312 (ε 12331)
max 276 (ε 13892)
max 274 (ε 12891)
2,4-(Cl)2-
4-NMe2-
3-NO2-
4-Me-
4 g
4 h
4 i
3-OMe-
4-F-
4 j
2-NO2-
4-OH-
4 k
Table 3. In vitro antibacterial activity of 3-[3-(substituted phenyl)-1-phenyl-1H-pyrazol-5-yl]-2H-chromen-2-one derivatives 4a–k (MIC
in µg/mL).
Gram-positive organisms
Gram-negative organisms
Compound
R
Staphylococcus aureus
Bacillus subtilis
Escherichia coli
Pseudomonas aeruginosa
4 a
H-
32
16
64
16
1
> 128
32
1
> 128
64
2
4 b
4-OMe-
4-Cl-
4 c
0.5
0.25
32
4 d
2,4-(Cl)2-
4-NMe2-
3-NO2-
4-Me-
3-OMe-
4-F-
0.5
64
2
1
1
4 e
> 128
4
> 128
8
4 f
2
4 g
4
8
2
1
4 h
0.25
0.25
0.25
0.5
64
64
0.5
0.5
1
0.5
1
4 i
4 j
2-NO2-
4-OH-
-
32
16
0.5
64
32
0.5
64
64
0.5
4 k
Ciprofloxacin
Journal of Enzyme Inhibition and Medicinal Chemistry

Synthesis of 3-(1H-pyrazol-5-yl)-2H-chromen-2-one derivatives 853
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Herein, we have described an efficient and convenient
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1-phenyl-1H-pyrazol-5-yl]-2H-chromen-2-one
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ese novel heterocyclic compounds containing both
coumarin and pyrazole ring systems are prepared by
the reaction of 3-[2,3-dibromo-3-(substituted phenyl)
propanoyl]-2H-chromen-2-one 3a–k with phenyl hydra-
zine in the presence of triethylamine in absolute ethanol.
In general, the results of the in vitro antibacterial activ-
ity tests are also encouraging as out of 11 compounds
tested, compounds 4d, 4h and 4i exhibited an antibac-
terial activity which is comparable or even more potent
than that of the reference drug. e MIC values of these
novel compounds evidenced that the presence of fluo-
rine, methoxy and chlorine groups at the third position
in the aromatic ring of the pyrazole nucleus gave rise to
an increased antibacterial potency.
acknowledgement
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e authors are thankful to Principal, RVS College of
Pharmaceutical Science, Sulur, Coimbatore, for provid-
ing necessary facilities to carry out this research work.
We are grateful to the Director, SAIF, Punjab University
for providing spectral analysis.
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Declaration of interest
e authors declare no conflict of interest.
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